Computational Screening of Anti-Cancer Drugs Identifies a New BRCA Independent Gene Expression Signature to Predict Breast Cancer Sensitivity to Cisplatin.

Abstract

Simple SummaryUsing a collection of publicly available drug screening resources, we identified different partners of genes associated with either sensitivity or resistance to 90 anti-cancer therapies. When subsequently applying these signatures to multiple datasets, we found that these predictive models could predict a large range of drug responses in patient samples. In particular, we discovered a new gene signature to identify breast cancer tumors that are likely to respond to cisplatin in the absence of BRCA1 mutations. This work constitutes an important advance to accelerate the application of platinum-based therapies in patient groups that are not routinely treated with these drugs. In the future, this approach may help to guide the choice of drugs based on the molecular profile of the tumors.The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer samples to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature for cisplatin can be used to identify tumors that are likely to respond to this drug, even in absence of the BRCA-1 mutation routinely used to select patients for platinum-based therapies. This clinically relevant observation was confirmed in multiple PDXs. Our study foreshadows an effective delivery approach for precision medicine.